Using metabotropic glutamate receptors to modulate cocaine's synaptic and behavioral effects: mGluR1 finds a niche.

Group I metabotropic glutamate receptors (mGluR) are important modulators of excitatory synaptic transmission and therefore potential targets for drug development. In several brain regions (ventral tegmental area (VTA), cerebellum, and amygdala), stimulation of mGluR1 selectively inhibits synaptic transmission mediated by calcium-permeable AMPA receptors (CP-AMPARs) and thus produces synaptic depression. The same relationship has now been demonstrated in the nucleus accumbens (NAc), a region that is critical for cocaine craving. CP-AMPAR levels in NAc synapses are normally low, but they increase after prolonged withdrawal from extended-access cocaine self-administration (SA). These CP-AMPARs mediate the intensified ('incubated') cue-induced cocaine craving observed under these conditions. Therefore, activation of mGluR1 with positive allosteric modulators (PAM) may reduce cue-induced relapse in abstinent cocaine addicts.